The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma

Abstract

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

“…Considering the extensive intertumoral heterogeneity in glioma, it is possible that NOTCH inhibition would be beneficial only in a proportion of molecularly selected patients in a personalized therapy. For instance, studies in vitro suggest that PTEN and TP53 status may affect sensitivity to GSIs in GBM [ 156 , 157 ]. NOTCH and EGF receptor pathways can potentiate each other in glioma cells [ 158 , 159 , 160 ] and, therefore, the oncogenic function of NOTCH signaling could be more apparent in primary GBMs of the classical subtype [ 161 ] than in GBMs with OPC-like proneural features [ 162 ] or IDH mutant LGGs [ 24 , 25 ].…”

Long-Term Inhibition of Notch in A-375 Melanoma Cells Enhances Tumor Growth Through the Enhancement of AXIN1, CSNK2A3, and CEBPA2 as Intermediate Genes in Wnt and Notch Pathways

“…Moreover, the relationship between the Notch, Wnt, and PI3K downstream genes is previously identified (50). Recently, Norihiko Saito and colleagues have reported that GSI resistance results from a change in oncogene addiction, from NOTCH to constitutive AKT in glioblastoma, and that the combination of GSIs and PI3K inhibitors may reduce tumor growth in glioblastoma (51).…”

Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer

“…Some recent data suggest that one mechanism may be connected with the downregulation of PTEN by activated NOTCH [56]. In some malignancies such as acute T-cell lymphoblastic leukemia, activation of the PI3K/AKT pathway downstream of NOTCH1 signaling promotes cell proliferation at multiple levels and has an important role in T-cell transformation [56,57]. Analysis of the transcriptional responses of GSI-sensitive PTEN wild-type glioblastoma cells to NOTCH inhibition showed significant upregulation of PTEN expression.…”

“…Analysis of the transcriptional responses of GSI-sensitive PTEN wild-type glioblastoma cells to NOTCH inhibition showed significant upregulation of PTEN expression. The authors demonstrated one possible mechanism of PTEN downregulation in vitro, which was mediated by HES1-a transcriptional repressor directly controlled by NOTCH [57].…”